New strategies are needed to improve the outcome of patients with adult glioblastoma multiforme (GBM). In addition to surgical resection (Rostomily et al. Baillieres Clin Neurol 5:345-369, 1996) and radiotherapy (Castro et al. Pharmacol Ther 98:71-108, 2003), numerous chemotherapeutic agents have been used to treat this disease (Parney et al. Cancer J 9:149-156, 2003), but limitations including poor central nervous system drug penetration and dose limiting toxicities have restricted their use (Rautioa et al. Curr Pharm Des 10:1341-1353, 2004). Temozolomide (TMZ), given orally as Temodar®, has been shown in randomized, placebo controlled, multi-institutional clinical trials, to be effective in prolonging survival and has received FDA approval for the treatment of newly diagnosed (Stupp et al. J Clin Oncol 20:1375-1382, 2002; Stupp et al. N Engl J Med 352:987-996, 2005) or recurrent (Yung et al. J Clin Oncol 17:2762-2771, 1999) malignant glioma. TMZ is an imidazotetrazine second-generation alkylating agent which, when given with radiation treatment has been shown to extend median survival 2.5 months compared to radiation alone (Stupp 2005) (Temodar® dose of 150-200 mg/m2). Higher doses of Temodar®, which might increase efficacy, are associated with dose-limiting myelosuppression including severe leukopenia and thrombocytopenia (Stupp 2002, 2005; Yung 1999; Gerber et al. Neuro Oncol 9:47-52, 2007). Research efforts have been directed towards local delivery of agents to the site of the tumor to achieve maximal drug concentrations while limiting toxicity. Recent advances in the local delivery of chemotherapeutic agents have shown encouraging results in the treatment of patients with malignant gliomas. See Attenello 2008; Soffietti et al. Anticancer Drugs 18:621-632, 2007; Raza et al. Expert Opin Biol Ther 5:477-494, 2005. While a number of therapeutic clinical trials are currently underway, there continues to be a limited number of agents in the armamentarium to effectively combat this disease. Gliadel®, a biodegradable polymer containing the alkylating agent Carmustine (BCNU), is implanted locally into the surgical bed at the time of high grade glioma resection, and has been shown to increase survival in both newly diagnosed (Brem et al. J Neurooncol 26:111-123, 1995; Westphal et al. Neuro Oncol 5:79-88, 2003; Valtonen et al. Neurosurgery 41:44-48, 1997; Westphal et al. Acta Neurochir (Wien) 148:269-275, 2006) and recurrent (Brem et al. Lancet 345:1008-1012, 1995) malignant gliomas. Alklyating agents, such as BCNU and TMZ, have clearly shown effective dose-response cytotoxicity for many glioma cell lines in vitro (Raza 2005; Wedge Anticancer Drugs 8:92-97, 1997). The maximal doses for each drug, however, are limited due to dose dependent systemic toxicity. To this end, Gliadel® is used to maximize local concentrations of BCNU and minimize systemic exposure. Based on similar principles and on the fact that systemic toxicity has been observed as a dose limiting factor for TMZ (Stupp 2005; Gerber 2007; Brock et al. Cancer Res 58:4363-4348, 1998), it has been shown in rodents that intracranial delivery of TMZ has improved efficacy when compared to the systemic administration of TMZ (Brem 2007).
Recent clinical evidence has suggested that treatment with a combination of modalities consisting of surgical excision, locally delivered BCNU, concurrent and adjuvant systemic TMZ, and radiotherapy is safe and effective, and provides improved survival compared to each treatment group alone. See Menei 2008; McGirt 2010; La Rocca 2008; Gururangan et al. Neuro Oncol 3:246-250, 2001; Pan et al. J Neurooncol 88:353-357, 2008. These clinical advances in glioma therapy, with multimodality treatments, have led to an improvement in expected survival for GBM from 9 to 20 months (Menei “Biodegradable carmustine-impregnated wafers (Gliadel®): the French experience”. Presented at the 8th Congress of the European Association of Neurooncology, Barcellona, Spain, Sep. 12-14, 2008; McGirt “Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme” J Neurosurg (2010 in press); La Rocca “A phase 2 study of multi-modal therapy with surgery, carmustine (BCNU) wafer, radiation therapy (RT), and temozolomide (TMZ) in patients (pts) with newly diagnosed supratentorial malignant glioma (MG)” Presented at the 8th Congress of the European Association of Neurooncology, Barcellona, Spain, Sep. 12-14, 2008; Attenello et al. Ann Surg Oncol 15:2887-2893, 2008.
Although the survival time has increased from nine to twenty months, on average, there remains a critical need for even greater prolongation of survival, preferably while maintaining the best possible quality of life.
It is therefore an object of the present invention to provide compositions providing significantly great efficacy in treating tumors, with far fewer side effects that limit the dosage that can be used, and cause patient discomfort.